Questions on cholesterol, atheroma and what a risk factor means

Question 1

Describe the formation of an atheroma, in order, from the first damage to the artery wall through to a fibrous plaque.

Accepted Answer

B1 the endothelium lining the vessel is damaged by mechanical stress from high blood pressure, particularly where arteries branch, by chemicals in tobacco smoke, by high blood glucose or by a high LDL concentration B1 LDL particles pass into the wall beneath the endothelium, are retained there and are chemically modified by oxidation, so they are treated as damage rather than as cargo B1 monocytes adhere to the activated endothelium and migrate into the wall, where they become macrophages B1 the macrophages take up modified LDL through receptors that are not regulated by how much cholesterol the cell already holds, so they keep eating, fill with lipid and become foam cells, and a collection of foam cells is a fatty streak B1 smooth muscle cells migrate from the deeper layers, multiply and deposit collagen over the accumulating lipid, forming a fibrous cap, so the plaque bulges into the lumen and narrows it

Question 2

The table gives results from a case-control study of first heart attacks, constructed for this question rather than measured. A health campaign concludes from it that reducing diabetes would prevent more heart attacks in this population than reducing high blood pressure, because diabetes has the larger odds ratio. Evaluate that conclusion.

Accepted Answer

B1 in support: the odds ratio does compare the strength of the two associations, and 2.4 against 1.9 means diabetes is the more strongly associated of the two with a first heart attack, each compared with people who lack that factor B1 against: how many cases a factor accounts for in a population depends on how common it is as well as on how strongly it acts, and high blood pressure is present in 30 per cent of these adults against 8 per cent with diabetes B1 against: an odds ratio is not a risk, because the investigators chose how many cases and how many controls to recruit, so neither group's risk can be read off this study at all, and for a common outcome an odds ratio sits further from 1 than the relative risk does B1 against: a risk factor is a variable associated with an increased probability of the disease in a population, which does not establish that it causes the disease or that removing it removes the risk, and the factors listed travel together, so their contributions cannot simply be added B1 judgement: the conclusion is not supported by the table. On these figures high blood pressure is the more promising target for a population despite its smaller odds ratio, and what either change would actually achieve needs a trial rather than a case-control study

Question 3

A systematic review of randomised trials found that reducing saturated fat intake cut combined cardiovascular events by about 17%, with no clear effect on death from any cause. A magazine reports the headline 'Cutting saturated fat doesn't save lives'. Evaluate this headline.

Accepted Answer

B1 in support: the review did find no clear effect on death from any cause, so the headline's specific factual claim about that particular outcome is not unreasonable on its own B1 in support: because the review is based on randomised trials rather than observational studies, its findings on both outcomes carry more weight against confounding than an association from a cohort study would B1 against: the same review found a real reduction, about 17 per cent, in combined cardiovascular events, which the headline omits entirely, giving a one-sided impression of the evidence B1 against: what a food is replaced with matters, since unsaturated fat looks beneficial while refined carbohydrate does not, and a headline about saturated fat alone says nothing about that choice B1 judgement: the headline is misleading rather than false; it reports the absence of one specific finding, an effect on overall mortality, as though it were the whole of the evidence, when the same trials also show a genuine benefit for cardiovascular events specifically

Question 4

Explain how the rupture of an atheroma in a coronary artery leads to the death of cardiac muscle.

Accepted Answer

B1 the fibrous cap tears, so collagen beneath it is exposed to the blood and platelets adhere and release thromboplastin B1 thromboplastin with calcium ions catalyses the conversion of prothrombin to thrombin, and thrombin catalyses the conversion of soluble fibrinogen into insoluble fibrin, which forms a mesh trapping cells B1 that clot can occlude the artery within minutes, so blood no longer reaches the muscle downstream of the blockage B1 the muscle is therefore deprived of oxygen and cannot respire aerobically, so its supply of ATP fails and the cells die, which is a myocardial infarction

Question 5

Compare LDL particles with HDL particles, referring to their composition, what each carries and where each takes it.

Accepted Answer

B1 both are lipoproteins, with a core of cholesteryl esters and triglyceride wrapped in a single layer of phospholipid carrying apoproteins, and the cholesterol inside each is chemically the same molecule B1 an LDL particle is larger and cholesterol-rich with relatively little protein, whereas an HDL particle is smaller and protein-rich, and since protein is dense that is why HDL is the denser class B1 LDL delivers cholesterol to any cell carrying LDL receptors, which take the whole particle in by receptor-mediated endocytosis, whereas HDL accepts cholesterol from cell membranes, including from cells inside artery walls B1 HDL carries what it collects back to the liver, which can excrete it in bile, so the two classes of particle run in opposite directions

Question 6

Explain why the evidence that a high LDL concentration causes atherosclerosis is regarded as much stronger than the evidence that a high HDL concentration protects against it.

Accepted Answer

B1 familial hypercholesterolaemia is caused by a fault in the gene for the LDL receptor and roughly doubles the blood LDL concentration from birth, producing heart attacks decades early, and that raised concentration was set at conception, so it cannot be a consequence of how the person lived B1 people carrying inactive versions of PCSK9 have lifelong LDL concentrations about a quarter lower and far less coronary heart disease, and because the variant is allocated at conception and is unrelated to income, smoking or diet the comparison behaves like a randomised trial B1 trials of drugs lowering LDL by unrelated mechanisms lower cardiovascular events in proportion to how much LDL they remove, so genetics, mechanism and trials all agree B1 for HDL only the observational association exists: drugs that raised HDL substantially did not reduce events, and genetic variants raising it are not associated with lower risk, so HDL appears to mark something protective rather than to be the protective thing itself

Question 7

A man's total blood cholesterol concentration is 6.4 mmol dm⁻³ and the cholesterol carried in his HDL particles is 1.2 mmol dm⁻³. Calculate his non-HDL cholesterol concentration, and calculate his total cholesterol concentration in milligrams per 100 cm³, taking the relative molecular mass of cholesterol as 386.7.

Accepted Answer

M1 the total counts the cholesterol carried in every class of particle, so the non-HDL concentration is the total minus the concentration carried in HDL A1 6.4 − 1.2 = 5.2 mmol dm⁻³ M1 mass concentration = concentration in mol dm⁻³ × relative molecular mass, so 6.4 × 10⁻³ × 386.7 = 2.47488 g dm⁻³ A1 1 dm³ is 1000 cm³, so 100 cm³ holds one tenth of that: 0.247488 g, which is 247 mg per 100 cm³ to three significant figures

Question 8

A man of 64 who smokes gets a cramping pain in his calf muscles after walking about a hundred metres, which goes when he stands still, and the pulse in that foot is weak. Suggest an explanation for these two observations, and suggest why he is also at raised risk of a stroke.

Accepted Answer

B1 an atheroma has formed in an artery supplying the leg, so the lumen is narrowed and the wall stiffened, less blood reaches the muscle each minute, and the pulse felt beyond the narrowing is weak B1 at rest the reduced supply is enough, but walking raises the muscle's demand for oxygen and the flow cannot rise to match it, so the muscle respires anaerobically and lactate accumulates and causes the pain B1 standing still lowers the demand again until the reduced supply can meet it, which is why the pain goes without anything about the artery having changed B1 atherosclerosis is not confined to one artery, because the same causes act on endothelium throughout the arterial system and the chemicals in tobacco smoke reach all of it, so a plaque in an artery supplying the brain is likely too; if its cap tears, a clot forms on it or a fragment breaks away as an embolus, brain tissue downstream is deprived of oxygen and dies, and that is a stroke

Question 9

Explain how an atheroma can lead to an aneurysm, and explain why the rupture of a large aneurysm in the abdominal aorta is usually fatal.

Accepted Answer

B1 a plaque weakens the section of artery wall it sits in, and the wall is carrying blood at high pressure B1 the weakened section stretches under that pressure, which thins it further and allows it to stretch even more, forming a localised bulge called an aneurysm B1 the abdominal aorta is one of the widest arteries in the body and carries a very large flow of blood at high pressure B1 if a large aneurysm there ruptures, blood is lost from the circulation catastrophically fast into the abdomen, faster than the body can compensate for, causing severe internal bleeding that is usually fatal

Question 10

A person's liver synthesises 950 mg of cholesterol a day and their gut absorbs a further 250 mg a day from food. Calculate the total amount of cholesterol entering their pool of cholesterol each day, and calculate what percentage of that total comes from the diet.

Accepted Answer

M1 total = liver synthesis + dietary intake = 950 + 250 A1 1200 mg per day M1 percentage from diet = dietary intake ÷ total × 100 = 250 ÷ 1200 × 100 A1 21 per cent, to two significant figures

Question 11

Compare cardiovascular risk factors that cannot be changed with those that can, giving two named examples of each and explaining why the distinction matters for using the term 'risk factor' responsibly.

Accepted Answer

B1 age, sex and family history cannot be changed by anything a person does, whereas smoking, high blood pressure and physical inactivity can be changed by treatment or by a change in behaviour B1 identifying a changeable risk factor, unlike an unchangeable one, opens the possibility of reducing an individual's risk by acting on it, such as by stopping smoking or by taking a drug that lowers blood pressure B1 an unchangeable risk factor such as age is still useful for prediction, contributing to an estimate of a person's ten-year risk, even though nothing can be done about the factor itself B1 because 'risk factor' only means 'associated with', not 'caused by' or 'fixable', calling something a risk factor does not by itself guarantee that changing it, where that is possible, will actually reduce the risk; that link needs separate evidence, ideally from a trial

Question 12

State what kind of lipid cholesterol is, and state what the body needs it for.

Accepted Answer

B1 it is a sterol, not a triglyceride: four fused carbon rings with a short hydrocarbon tail at one end and a single hydroxyl group at the other B1 it regulates the fluidity of every cell-surface membrane, restricting movement of the phospholipids at higher temperatures and preventing them packing too closely at lower ones B1 it is the precursor of the steroid hormones and of the bile salts, and the starting material for vitamin D

Question 13

Explain why a statin lowers blood cholesterol concentration far more effectively than simply eating less cholesterol does.

Accepted Answer

B1 the liver synthesises roughly a gram of cholesterol a day, several times more than a typical diet supplies, and reduces its own synthesis when dietary intake rises, so eating less dietary cholesterol is partly offset by the liver making more B1 a statin instead inhibits HMG-CoA reductase, the rate-limiting enzyme of the liver's own cholesterol synthesis pathway, directly reducing the much larger internal source B1 because the liver's own synthesis is the dominant source of blood cholesterol and a statin acts on it directly, while diet acts on the smaller source the liver partly compensates for anyway, the drug produces a far bigger fall in blood cholesterol concentration

Question 14

Triglyceride absorbed from a meal leaves the ileum in particles called chylomicrons, and triglyceride made in the liver travels in particles called VLDL. Each particle has a core of triglyceride and cholesterol surrounded by a single layer of phospholipid molecules, with proteins in its surface. Explain why triglyceride has to be carried in such particles, and explain the arrangement of the phospholipids in the outer layer.

Accepted Answer

B1 triglyceride is non-polar and insoluble in water, so it cannot dissolve in plasma, which is mostly water B1 the hydrophilic phosphate heads of the phospholipids face outwards into the watery plasma and their hydrophobic fatty acid tails face inwards towards the lipid core B1 one layer is enough because the inside of the particle is lipid, not water: unlike a membrane bilayer, which has water on both sides, only its outer surface faces water

Question 15

A man is diagnosed with familial hypercholesterolaemia after a heart attack at 42. Suggest why his doctor recommends that his children should also have their blood cholesterol tested, even though they currently have no symptoms.

Accepted Answer

B1 familial hypercholesterolaemia is caused by a fault in the gene for the LDL receptor, so his children each have a chance of having inherited the same faulty gene from him B1 a raised LDL concentration caused by this condition is present from birth and produces no symptoms for decades before a heart attack occurs, so waiting for symptoms would mean missing the chance to act early B1 testing while young and without symptoms allows any child who has inherited the condition to be identified and treated, for example with a statin, years before the arteries have accumulated the decades of damage that led to their father's early heart attack

Risk factor	Odds ratio for a first heart attack	Percentage of adults in this population with the factor
Abnormal blood lipids	3.3	45
Current smoking	2.9	26
Diabetes	2.4	8
Abdominal obesity	2.2	33
High blood pressure	1.9	30